HRP20150340T1 - Oligosaccharide-protein conjugates - Google Patents

Oligosaccharide-protein conjugates Download PDF

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HRP20150340T1
HRP20150340T1 HRP20150340TT HRP20150340T HRP20150340T1 HR P20150340 T1 HRP20150340 T1 HR P20150340T1 HR P20150340T T HRP20150340T T HR P20150340TT HR P20150340 T HRP20150340 T HR P20150340T HR P20150340 T1 HRP20150340 T1 HR P20150340T1
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Croatia
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compound
formula
fluoride
image
hydroxyl
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HRP20150340TT
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Croatian (hr)
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Clark Pan
Xiaoyang Zheng
Robert J. Miller
Joseph Kutzko
Yunxiang Zhu
Duncan PATTERSON
Andreas PEER
Paul A. Konowicz
Luis Z. Avila
James E Stefano
Michael R. Reardon
John Harrahy
Qun Zhou
Lauren Young
Patrick Finn
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Genzyme Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Claims (21)

1. Postupak za pripravu spoja koji ima Formulu VIIA: [image] pri čemu: R1 je odabran od vodika, hidroksila, po izboru supstituirana alkilna skupina koja ima 1 do 4 atoma ugljika, fosfat, sulfat, -OR7, zaštitna skupina, te saharid; R2, R3, R4, i R5 su svaki neovisno odabrani od vodika, sulfata, hidroksila, -OR8, zaštitne skupine i saharida; R6 je odabran od vodika, hidroksila, karboksila, alkoksikarbonila, amino, amida, alkilamino, aminoalkila, aminoksi, hidrazida, hidrazina, po izboru supstituiranog alkenila, te po izboru supstituiranog C2-C6 alkila; R7 i R8 su svaki neovisno odabrani od acetila i po izboru supstituirane alkilne skupine koja ima 1 do 4 atoma ugljika; i n je cijeli broj od 1 do 10; naznačen time da sadrži: a) obradu spoja koji ima Formulu VIIIA: [image] pri čemu: R1 do R5 su kako je gore definirano; i R9 i R10 su odabrani od vodika i hidroksila, tako da kada jedan od R9 i R10 je hidroksil, drugi je vodik; sa spojem koji ima Formulu R11R12(Sn=O) da se dobije spoj s Formulom IXA: [image] pri čemu: R1 do R5 su kako je gore definirano; i R11 i R12 su svaki neovisno odabrani između nesupstituiranog alkila, ili R11 i R12, uzeti zajedno, su odabrani od nesupstituiranog alkilena; te b) obradu spoja s Formulom IXA, proizvoljno u prisutnosti metalnog halida, sa spojem koji ima Formulu R6-(CH2)n-L, pri čemu: R6 i n su kako je gore definirano; i L je halogen; da se dobije spoj s Formulom VIIA.1. Process for preparing a compound having Formula VIIA: [image] whereby: R1 is selected from hydrogen, hydroxyl, an optionally substituted alkyl group having 1 to 4 carbon atoms, phosphate, sulfate, -OR7, a protecting group, and saccharide; R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, sulfate, hydroxyl, -OR 8 , a protecting group, and saccharide; R6 is selected from hydrogen, hydroxyl, carboxyl, alkoxycarbonyl, amino, amide, alkylamino, aminoalkyl, aminooxy, hydrazide, hydrazine, optionally substituted alkenyl, and optionally substituted C2-C6 alkyl; R 7 and R 8 are each independently selected from acetyl and an optionally substituted alkyl group having 1 to 4 carbon atoms; and n is an integer from 1 to 10; characterized by containing: a) treatment of the compound having Formula VIIIA: [image] whereby: R1 to R5 are as defined above; and R 9 and R 10 are selected from hydrogen and hydroxyl, such that when one of R 9 and R 10 is hydroxyl, the other is hydrogen; with a compound of Formula R11R12(Sn=O) to give a compound of Formula IXA: [image] whereby: R1 to R5 are as defined above; and R 11 and R 12 are each independently selected from unsubstituted alkyl, or R 11 and R 12 taken together are selected from unsubstituted alkylene; you b) treatment of a compound of Formula IXA, optionally in the presence of a metal halide, with a compound of Formula R6-(CH2)n-L, whereby: R 6 and n are as defined above; and L is halogen; to obtain a compound of Formula VIIA. 2. Postupak prema zahtjevu 1, naznačen time da R6 je alkoksikarbonil.2. The method according to claim 1, characterized in that R6 is alkoxycarbonyl. 3. Postupak prema zahtjevu 1, naznačen time da n je 2, 3, 4, 5, ili 6 i R6 je C1-C4 alkoksikarbonil.3. The method according to claim 1, characterized in that n is 2, 3, 4, 5, or 6 and R6 is C1-C4 alkoxycarbonyl. 4. Postupak prema zahtjevu 1, naznačen time da n je 3 i R6 je metoksikarbonil.4. The method according to claim 1, characterized in that n is 3 and R6 is methoxycarbonyl. 5. Postupak prema zahtjevu 1, naznačen time da spoj s Formulom R6-(CH2)n-L je metil 4-bromobutirat.5. The method according to claim 1, characterized in that the compound with Formula R6-(CH2)n-L is methyl 4-bromobutyrate. 6. Postupak prema zahtjevu 1, naznačen time da je spoj s Formulom VIIIA odabran od proizvoljno zaštićene manoze, ramnoze, idoze i altroze.6. Process according to claim 1, characterized in that the compound with Formula VIIIA is selected from arbitrarily protected mannose, rhamnose, idose and altrose. 7. Postupak prema zahtjevu 5 ili zahtjevu 6, naznačen time da spoj s Formulom VIIIA je proizvoljno zaštićena manoza.7. The method according to claim 5 or claim 6, characterized in that the compound with Formula VIIIA is an arbitrarily protected mannose. 8. Postupak prema zahtjevu 1, naznačen time da metalni halid je metalni fluorid.8. The method according to claim 1, characterized in that the metal halide is a metal fluoride. 9. Postupak prema zahtjevu 8, naznačen time da je metalni fluorid odabran od cezijevog fluorida, natrijevog fluorida, kalcijevog fluorida, magnezijevog fluorida, litijevog fluorida, te kalijevog fluorida.9. The method according to claim 8, characterized in that the metal fluoride is selected from cesium fluoride, sodium fluoride, calcium fluoride, magnesium fluoride, lithium fluoride, and potassium fluoride. 10. Postupak prema zahtjevu 1, naznačen time da korak b dodatno sadrži reakciju spoja s Formulom IXA u prisutnosti tetraalkilamonijevog halida.10. The method according to claim 1, characterized in that step b additionally contains the reaction of the compound with Formula IXA in the presence of tetraalkylammonium halide. 11. Postupak prema zahtjevu 10, naznačen time da tetraalkilamonijev halid je tetrabutilamonijev jodid.11. The method according to claim 10, characterized in that the tetraalkylammonium halide is tetrabutylammonium iodide. 12. Postupak prema zahtjevu 1, naznačen time da R11 i R12 svaki su butil, R11 i R12 svaki su heksil, ili R11 i R12, uzeti zajedno, tvore heksametilen.12. The process according to claim 1, characterized in that R11 and R12 are each butyl, R11 and R12 are each hexyl, or R11 and R12, taken together, form hexamethylene. 13. Postupak prema zahtjevu 1, naznačen time da spoj s Formulom VIIIA je odabran od 3,4,6-tri-O-benzil-D-manoze i 3-O-alil-6-O-tritil-D-manoze.13. The method according to claim 1, characterized in that the compound with Formula VIIIA is selected from 3,4,6-tri-O-benzyl-D-mannose and 3-O-allyl-6-O-trityl-D-mannose. 14. Postupak prema zahtjevu 13, naznačen time da spoj s Formulom VIIIA je 3-O-alil-6-O-tritil-D-manoza.14. The method according to claim 13, characterized in that the compound with Formula VIIIA is 3-O-allyl-6-O-trityl-D-mannose. 15. Postupak prema zahtjevu 1, naznačen time da spoj s Formulom VIIA je [image] .15. The method according to claim 1, characterized in that the compound with Formula VIIA is [image] . 16. Postupak prema zahtjevu 1, naznačen time da dodatno sadrži uzastopno dodavanje barem jednog monosaharida u spoj s Formulom VIIA da se dobije oligosaharid.16. The method according to claim 1, characterized in that it further comprises the sequential addition of at least one monosaccharide to the compound of Formula VIIA to obtain an oligosaccharide. 17. Postupak prema zahtjevu 16, naznačen time da oligosaharid je heksasaharid.17. The method according to claim 16, characterized in that the oligosaccharide is a hexasaccharide. 18. Postupak prema zahtjevu 17, naznačen time da heksasaharid je [image] 18. The method according to claim 17, characterized in that the hexasaccharide is [image] 19. Postupak prema zahtjevu 1, naznačen time da R6 je aminoksi.19. The method according to claim 1, characterized in that R6 is aminooxy. 20. Postupak prema zahtjevu 1, naznačen time da dodatno sadrži korak mijenjanja položaja i identiteta zaštitnih skupina u navedenom spoju, uključujući dodavanje dodatnih zaštitnih skupina navedenom spoju.20. The method according to claim 1, characterized in that it additionally contains the step of changing the position and identity of protective groups in the specified compound, including adding additional protective groups to the specified compound. 21. Postupak prema zahtjevu 20, naznačen time da proizvod navedenog postupka je spoj s Formulom [image] .21. The process according to claim 20, characterized in that the product of the mentioned process is a compound with Formula [image] .
HRP20150340TT 2008-12-16 2015-03-25 Oligosaccharide-protein conjugates HRP20150340T1 (en)

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US12285108P 2008-12-16 2008-12-16
EP12160009.2A EP2465542B1 (en) 2008-12-16 2009-12-11 Oligosaccharide-protein conjugates

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